ZA200500049B - Process for preparing 5-(4-fluorophenyl)-1-2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide - Google Patents

Process for preparing 5-(4-fluorophenyl)-1-2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide Download PDF

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ZA200500049B
ZA200500049B ZA200500049A ZA200500049A ZA200500049B ZA 200500049 B ZA200500049 B ZA 200500049B ZA 200500049 A ZA200500049 A ZA 200500049A ZA 200500049 A ZA200500049 A ZA 200500049A ZA 200500049 B ZA200500049 B ZA 200500049B
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compound
formula
solvent
transition metal
base
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ZA200500049A
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Jade Nelson
Pamment Douglas
Gerard Michael
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Warner Lamert Company Llc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/06—Antihyperlipidemics

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Description

PROCESS FOR PREPARING 5-(4-FLUOROPHENYL)-1-[2-((2R,4R)-4-
HYDROXY-6-OXO-TETRAHYDRO-PYRAN-2-YL) ETHYL]-2-IS OPROPYL- . 4-PHENYL-1H-PYRROLE-3-CARBOXYLIC ACID PHENYLAMIDE ) 5 CROSS REFERENCE TO RELATED APPLICATIONS
This application claims benefit of priority from United States Provisional
Application Number 60/401,707 filed on August 6,2002.
FIELD OF THE INVENTION
A method for preparing 5-(4-fluorophenyl)-1-[2-((2R 4R)-4-hydroxy-6- oxo-tetrahydro-pyran-2-yl)-ethyl}-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide, a key intermediate in the synthesis of atorvastatin calcium, is described.
BACKGROUND OF THE INVENTION
5-(4-Fluorophenyl)-1 _[2-((2R 4R)-4-hydroxy-6-oxo-tetrahydro-pyran- 2-yl)-ethyl]-2-isopropyl-4-phenyl-1H -pyrrole-3-carboxylic acid phenylamide (I) is a key intermediate in the synthesis of atorvastatin calcium (Lipitor®), known also by the chemical name [R-(R* R*)]-2-(4-fluorophenyl)-B,5-dihydroxy-5-(1- methylethyl)-3-phenyl-4-[(phenyl amino)carbonyl}- 1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate. Atorvastatin calcium inhibits 3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and thus is useful as a hypolipidemic and/or hypocholesterolemic agent.
F F
O >
Qa — | Qe | a0 oN “OH oN OH . N Me N Me Ca* 0 me 9 O Me
I
2
Atorvastatin Calcium
A number of patents have issued disclosing atorvastatin, as well as . processes and key intermediates for preparing atorvastatin. These include: United
States Patent Nos. 4,681,893, 5,273,995, 5,003,080; 5,097,045, 5,103,024, . 5 5,124,482, 5,149,837, 5,155,251, 5,216,174, 5,245,047, 5,248,793, 5,280,126, 5,397,792, 5,342,952, 5,298,627, 5,446,054, 5,470,981, 5,489,690, 5,489,691, 5,510,488, 5,998,633, 6,087,511, 5,969,156, 6,121,461, 5,273,995 6,476,235, 5,969,156, and 6,121,461.
Existing approaches to the preparation of key intermediate (I) presented some shortcomings. For example, one approach relied on the use of a costly chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction.
Scheme 1 summarizes an alternative approach disclosed in United States
Patent No. United States Patent No. 6,476,235. Hydrogenation of B.0 diketoester 2 in the presence of a chiral ruthenium catalyst under acidic conditions proceeded to give diol 3 in moderate to good yields and 1:1 syn:anti diastereoselectivity with respect to the C-3 and C-5 chiral centers. A number of additional transformations are then necessary to reset the stereochemistry of the C-3 center in diol 3 to provide key intermediate (I). These steps include: (a) intramolecular cyclization of 3 to provide lactone 4; (b) elimination of water from lactone 4 to provide o,f unsaturated lactone 5; ©) facial selective Michael addition of allyl or benzyl alcohol to ¢.,B unsaturated lactone 5 to provide saturated lactone 6; and removal of the allyl or benzyl moiety in lactone 6 via hydrogenolysis provided key intermediate (I).
Scheme 1
F F
2) } Oo 0 © ) OH OH O
H = H —
N Me N Me bw bu 2 3
F F
OI Jf al ALT) y — 7
N OH N
H = H —
N Me N Me
ORL © on
F
OD 3 aL 1 em 4 . '
Ym 6 R'= benzyl, allyl '
H — N OR Cs R'=H
N Me oil
As a preliminary matter, the asymmetric hydrogenation of ketones isa 5 known transformation in organic synthesis. However, the complexity of the reaction increases in the case of 1,3,5-tricarbonyl systems, and poor yields and poor stereoselectivities often result. In fact, investigations by Saburi (Tetrahedron, 1997, 1993;49) and Carpentier (Eur. J. Org. Chem. 1999;3421) have independently demonstrated low to moderate diastereo- and/or enantio- selectivities for diketoester asymmetric hydrogenations. : Furthermore, the fact that the processes disclosed in the literature require high pressure hydrogenation and extended reaction times makes the procedures : generally impractical and not amenable to large-scale manufacturing processes where safety, efficiency, and cost are critical considerations.
As a result, a need remains for an approach to the preparation of key intermediate (I) that is efficient, inexpensive, proceeds in a minimum of ; transformations, and occurs in good yield and high levels of diastereoselectivity. : 5 SUMMARY OF THE INVENTION
These and other needs are met by the present invention which is directed to a process for the preparation of a compound of formula (I)
F
Jf $ DO.
PP 7)
N ‘OH
H =(
N —Me 9! OMe 1 comprising: (a) contacting in a solvent a compound of formula (II) with a transition metal catalyst, a hydrogen source, and a base to give a compound of formula (III): . F | F 2) oO oO O $ OH OH O
N R'_ “> N R!
H = H —
N Me N Me @! O Mme : @! O Me. 1 mn wherein
RI is defined as —XR, wherein X is O,
S, or Se, or
N—R?
Rlis 3 , wherein R2 and R3 are independently alkyl,
R cycloalkyl, arylalkyl, or ; aryl, or
R2 and R3 taken together are -(CH2)4-, -(CH»)s5-, ~(CH(R%)-CHp)3-, -(CHRH-CH»)4-, -(CH(R*)-(CHp)2-CHRY))-, -(CH(R*)-(CH2)3-CHR?)-, -CH,-CH»-A-CHp-CHp-, -CH(R#%)-CHj-A-CHyCHo-, _CH(R%)-CHj-A-CHy-CH(R#)-, wherein R* is alkyl of from one to four carbon atoms, A is O, S, or NH or NR wherein R is defined as alkyl, aryl, arylalkyl, or heteroaryl; (b) conversion of the compound of formula (IIT) wherein R!is as defined above to a compound of formula (IV) using base;
F F
OH OH O ® ) PUSSY $ OH OH O
N Al ———— AGIA
H —_ ! _ N OH
N Me N Me ob bu
AY, and . and (©) contacting in a solvent the compound of formula (IV) with an acid to afford a compound of Formula (I).
The invention also provides a process for the preparation of a compound of formula (I) . F
J 3
J Ne
YZ .
N “OH
H —_
N Me (bu
I comprising: (a) contacting in a solvent compound of formula (V) with a transition metal catalyst, a hydrogen source, and a base to give a compound of formula (VI):
F : F $ oO 0 © @ OH OH ©
N OR. N OR"
H m= H —_
N Me N Me
Oe O ow vo Vi wherein
R” is defined as Me, Et, or t-Bu; (b) conversion of the compound of formula (VI) wherein R"is as defined above to a compound of formula (IV) using base;
F F oh QO
CO) P PSP | 7) OH OH O as RF ———— & AAA : N Me N = Me
P O me ! O Me
Vi Vv and (©) contacting in a solvent the compound of formula (IV) with an acid to afford a compound of Formula (I).
As disclosed herein, we surprisingly and unexpectedly found that the diol esters of the present invention, (R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid esters, can be obtained directly from the corresponding 1,3,5-tricarbonyl precursors in a highly stereoselective manner via a mild and efficient ruthenium-catalyzed asymmetric transfer hydrogenation reaction utilizing transition metal catalysts with chiral non- racemic ligands. The reaction proceeds in good yields at ambient temperature and atmospheric pressure. The invention process is thus safer and more efficient in large scale than earlier approaches, because it avoids the need for specialized high pressure equipment and the use of hydrogen gas. Because the transfer hydrogenation reaction occurs with high levels of syn diastereoselectivity, additional transformations are not necessary to correct the stereochemistry of the
C-3 center, as in previous approaches, and the overall number of steps needed to convert the compound of formula (II) to key intermediate (I) is minimized.
Moreover, the invention process avoids the use of a costly, chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction, as was necessary in earlier approaches to the preparation of key intermediate (I).
DETAILED DESCRIPTION OF THE INVENTION Definitions
The term “alkyl” means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, . 5 isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term “cycloalkyl” means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, : cyclohexyl, cycloheptyl, cyclooctyl, and the like. “Alkoxy” and “thioalkoxy” are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for “alkyl”.
The term “aryl” means an aromatic radical which is a phenyl group, a phenylalkyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano, 0) —LLNaiky as defined above for alkyl, -(CHa)p,-N(alkyl), wherein n; is an integer of from 1 to 5 and alkyl is as defined above o (CHaIny—N-1 alkyl and alkyl as defined above for alkyl and no.
The term “heteroaryl” means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a benzene ring containing 1 to 3 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3- thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2- pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5- yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, or 2- or 5-thiadiazolyl and the like optionally substituted by a substituent selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano,
O
—LLN(alkyD2 a5 defined above for alkyl, -(CHz)nz-N(alkyl)y wherein ns is an
Oo (CHang—N-1alkyl integer of 1 to 5, and alkyl is as defined above, and as alky! as defined above for alkyl and na.
The term “arylalkyl” means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above for example, benzyl, phenylethyl, 3-phenylpropyl, (4-chlorophenyl)methyl, and the like.
Description of Invention Process
The invention process disclosed herein is depicted in Scheme 2 and commences in step (a) with transfer hydrogenation of a compound of formula (II)
A to form a compound of formula (IIT). In step (b), the Rt moiety (typically, an ester or an amide) in the compound of formula (III) is hydrolyzed to form the acid (IV). Finally, in step (c), lactonization of the acid (IV) provides key intermediate (I).
Scheme 2
F F
$ 0 0 © 4 OH OH ©
ZF ~ANN 1 (a) & AN 1
N Me N Me om vat
L 0
F
F
> 0 3 4 OH OH O o (b) & Aon —. 4 2 . — He N "OH
N H
Me N @! 0 me Me
P O we
AY

Claims (13)

  1. CLAIMS .
  2. What is claimed is:
  3. : I.
  4. A process for the preparation of a compound of formula (I) F J 3 ALD) Z " N ‘OH H — N Me bo
  5. 5 . - 1 comprising: (a) contacting in a solvent a compound of formula (II) with a transition metal catalyst, a hydrogen source, and a base to give a compound of formula (II): F F @ O O © @ » OH OH © Z ~ ANN ~ANN N R! I & N R! H == H _ N Me N Me Go SATA 1 in wherein R1 is defined as —XR, wherein X is O, S, or Se, or Rlis | , wherein R2 and R3 are independently alkyl, R3 cycloalkyl, arylalkyl, or aryl, or
    R2 and R3 taken together are -(CH2)4-, -(CH2)s-, -(CH(R4)-CH»)3-, -(CH(R#%)-CH3)4-, -(CHR#)-(CH2)2-CHR4)-, -(CH(R*)-(CH2)3-CHR4)-, -CH»-CH3-A-CH-CHjp-, -CHR#-CH,-A-CH)CH>-, _CH(R4)-CH3-A-CH-CH(RY)-, wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or NH or NR wherein R is defined as alkyl, aryl, arylalkyl, or heteroaryl; (b) conversion of the compound of formula (III) wherein R'is as defined above to a compound of formula (IV) using base in aqueous methanol; F F 4 OH OH © 4 J OH OH © AANA AAA N Rn H — N OH N Ho = Me N Me ORL of bu I v and (©) contacting in a solvent the compound of formula (IV) with an acid to afford a compound of Formula (I).
    2. The process of claim 1, wherein contacting in step (a) comprises mixing the compound of formula I, formic acid, base, and transition metal catalyst in a solvent to form a homogeneous or heterogeneous mixture, wherein the solvent is an aqueous or . anhydrous polar aprotic, polar protic, or nonpolar solvent selected from acetone, pentane, hexane, methylethyl ketone, : 5 tetrahydrofuran, dimethyl formamide, diethyl ether, methylene chloride, chloroform, methanol, ethanol, isopropanol, and toluene, acetonitrile, ethyl acetate, water, or mixtures or combinations thereof.
    3. The process of claim 1, wherein in the compound of formula Ii or III, R1 Co : is defined as —XR, wherein X is O and R is alkyl, cycloalkyl, arylalkyl, aryl, or heteroaryl.
    4. The process of claim 1, wherein in the compound of formula II or 110, R! is defined as —-XR, wherein X is O and R is alkyl.
    5. The process of claim 1, wherein in the compound of formula II or II, R1 is OMe, OEt, or Ot-Bu.
  6. 6. The process of claim 1, wherein the transition metal catalyst in step (a) is derived from Ir, Ru, or Rh and is prepared from a transition metal catalyst precursor selected from [dichloro-(1,5-cycloocta- diene)] ruthenium (II) oligomer, [RuCl benzene], , [RuClyp-cymene]s, [RuCl, mesitylene]o, [dibromo-(1,5-cyclooctadiene)] ruthenium (II) dimer, [bis-(2- methallyl)cycloocta-1,5-diene] ruthenium (II) complex, pentamethylcyclopenta- dienyl iridium (I)chloride dimer, and pentamethylcyclopentadienyl rhodium (I)chloride dimmer and a chiral, non racemic ligand which is a chiral diamine ligand or a chiral alcohol amine ligand selected from norephedrine or compounds 7 or 8.
    : oy ree HN LF Dae se : ) R3=Alkyl, heteroaryl, 7 8 or aryl
  7. 7. The process of step (a) of claim 1 wherein the transition metai catalyst is Ruthenium, [N-[(1R,2R)-2-(amino-kN)-1,2- diphenylethyl}-4-methylbenzenesulfonamidato- KN]jchloro[(1,2,3,4,5,6-n)-1,3,5-trimethylbenzene]-
  8. 8. The process of claim 1, wherein the hydrogen source in step (a) is selected from formic acid, ammonium formate, and isopropanol, the base in step (a) is an amine base selected from triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0.] undec-7-ene - (DBU), lutidine, collidine, 4-dimethylaminomethyl pyridine, diisopropyl amine, tri-n-butyl amine,4-methylmorpholine, piperidine, and pyrrolidine.
  9. 9. The process of claim 1, wherein the concentration of the compound of formula (II) in the solvent in step (a) is about 0.2 Molar to about
    0.6 Molar and the molar equivalents of each of the compound of formula (II) used is about 1; of the hydrogen source, the base, and the transition metal catalyst are: about 1 equivalent of the compound of formula (II); : about 2.0 to about 2.5 equivalents of hydrogen source; about 4.0 to about 5.0 equivalents of amine base; and ) about 0.05 to about 2 mol percent of the transition metal catalyst..
  10. 10. The process of claim 1, wherein the concentration of the compound of formula (IT) in the solvent in step (a) in the solvent is about 0.35 . Molar to about 0.45 Molar and the molar equivalents of each of the compound of formula (II) used is about 1; of the hydrogen source, . 5 the base, and the transition metal catalyst are: about 1 equivalent of the compound of formula (II); about 2.1 to about 2.4 equivalents of hydrogen source; about 4.1 to about 4.8 equivalents of amine base; and about 1 mol percent of the transition metal catalyst. :
  11. 11. The process of claim 1, wherein the reaction temperature in step (a) is about 0 to about 50 °C, the reaction pressure of step (a) is about
    0.9 to about 1.1 atmospheres, and the reaction time of step (a) is about 6 to about 24 hours.
  12. 12. The process of claim 1, wherein the reaction temperature in step (a) is about 20 to about 30 °C, the reaction pressure of step (a) is about
    0.95 to about 1.05 atmospheres, and the reaction time of step (a) is about 12 to about 18 hours.
  13. 13. The process of claim 1, wherein step (a) comprises contacting in a solvent compound of formula (V) with a transition metal catalyst, a hydrogen source, and a base to give a compound of formula (VI): F F oO oo o OH OH © ¢ AAA & AA on H ES H — N Me N Me @ O m¢ 9! O Mé Vv vi wherein R” is defined as Me, Et, or t-Bu.
ZA200500049A 2002-08-06 2005-01-04 Process for preparing 5-(4-fluorophenyl)-1-2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide ZA200500049B (en)

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ES2287549T3 (en) * 2002-08-06 2007-12-16 Warner-Lambert Company Llc PROCEDURE TO PREPARE ACID PHENYLAMIDE 5- (4-FLUOROPHENYL) -1- (2 - ((2R, 4R) -4-HIDROXI-6-OXO-TETRAHIDROPIRAN-2-IL) ETIL) -2-ISOPROPIL-4- FENIL-1H-PIRROL-3-CARBOXILICO.
EP1615883A1 (en) * 2003-04-14 2006-01-18 Warner-Lambert Company Process for preparing 5-(4-fluorophenyl)-1-[2-((2r,4r)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide
CA2526730A1 (en) 2003-05-30 2004-12-09 Ranbaxy Laboratories Limited Substituted pyrrole derivatives
SG166829A1 (en) 2005-11-08 2010-12-29 Ranbaxy Lab Ltd Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt
JP4077863B1 (en) 2007-05-31 2008-04-23 タヒボジャパン株式会社 Process for producing optically active 2- (1-hydroxyethyl) -5-hydroxynaphtho [2,3-b] furan-4,9-dione having anticancer activity
CN101205209B (en) * 2007-12-25 2010-06-02 浙江新东港药业股份有限公司 Method for refining atorvastatin intermediate
WO2011028309A1 (en) 2009-09-04 2011-03-10 University Of Toledo PROCESSES FOR PRODUCING OPTICALLY PURE β-LACTONES FROM ALDEHYDES AND COMPOSITIONS PRODUCED THEREBY
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